The present invention relates to certain 6-phenylpyridyl-2-amine derivatives that exhibit activity as nitric oxide synthase (NOS) inhibitors, to pharmaceutical compositions containing them and to their use in the treatment and prevention of central nervous system disorders, inflammatory disorders, septic shock and other disorders.
There are three known isoforms of NOSxe2x80x94an inducible form ([-NOS) and two constitutive forms referred to as, respectively, neuronal NOS (N-NOS) and endothelial NOS (E-NOS). Each of these enzymes carries out the conversion of arginine to citrulline while producing a molecule of nitric oxide (NO) in response to various stimuli. It is believed that excess nitric oxide (NO) production by NOS plays a role in the pathology of a number of disorders and conditions in mammals. For example, NO produced by I-NOS is thought to play a role in diseases that involve systemic hypotension such as toxic shock and therapy with certain cytokines. It has been shown that cancer patients treated with cytokines such as interleukin 1 (IL-1), interleukin 2 (IL-2) or tumor necrosis factor (TNF) suffer cytokine-induced shock and hypotension due to NO produced from macrophages, i.e., inducible NOS (I-NOS), see Chemical and Engineering News, Dec. 20, p. 33, (1993). I-NOS inhibitors can reverse this. It is also believed that I-NOS plays a role in the pathology of diseases of the central nervous system such as ischemia. For example, inhibition of I-NOS has been shown to ameliorate cerebral ischemic damage in rats, see Am. J. Physiol., 268, p.
R286 (1995)). Suppression of adjuvant induced arthritis by selective inhibition of I-NOS is reported in Eur. J. Pharmacol., 273, p. 15-24 (1995).
NO produced by N-NOS is thought to play a role in diseases such as cerebral ischemia, pain, and opiate tolerance. For example, inhibition of N-NOS decreases infarct volume after proximal middle cerebral artery occlusion in the rat, see J. Cerebr. Blood Flow Metab., 14, p. 924-929 (1994). N-NOS inhibition has also been shown to be effective in antinociception, as evidenced by activity in the late phase of the formalin-induced hindpaw licking and acetic acid-induced abdominal constriction assays, see Br. J. Pharmacol., 110, p. 219-224 (1993). Finally, opioid withdrawal in rodents has been reported to be reduced by N-NOS inhibition, see Neuropsychopharmacol., 13, p. 269-293 (1995).
This invention relates to compounds of the formula 
and the pharmaceutically acceptable salts thereof, wherein
R1 and R2 are selected, independently, from (C1-C6) alkyl, tetrahydronaphthalene and aralkyl, wherein the aryl moiety of said aralkyl is phenyl or naphthyl and the alkyl moiety is straight or branched and contains from 1 to 6 carbon atoms, and wherein said (C1-C6) alkyl and said tetrahydronaphthalene and the aryl moiety of said aralkyl may optionally be substituted with from one to three substituents, preferably from zero to two substituents, that are selected, independently, from halo (e.g., chloro, fluoro, bromo, iodo), nitro, hydroxy, cyano, amino, (C1-C4) alkoxy, and (C1-C4) alkylamino;
or R1 and R2 form, together with the nitrogen to which they are attached, a piperazine, piperidine or pyrrolidine ring or an azabicyclic ring containing from 6 to 14 ring members, from 1 to 3 of which are nitrogen and the rest of which are carbon, wherein examples of said azabicyclic rings are the following 
wherein R3 and R4 are selected from hydrogen, (C1-C6)alkyl, phenyl, naphthyl, (C1-C6)alkyl-C(xe2x95x90O)xe2x80x94, HC(xe2x95x90O)xe2x80x94, (C1-C6)alkoxy-(Cxe2x95x90O)xe2x80x94, phenyl-C(xe2x95x90O)xe2x80x94, naphthyl-C(xe2x95x90O)xe2x80x94, and R7R8NC(xe2x95x90O)xe2x80x94 wherein R7 and R8 are selected, independently, from hydrogen and (C1-C6)alkyl;
R5 is selected from hydrogen, (C1-C6)alkyl, phenyl, naphthyl, phenyl-(C1-C6)alkyl- and naphthyl(C1-C6)alkyl-;
and wherein said piperazine, piperidine and pyrrolidine rings may optionally be substituted with one or more substituents, preferably with from zero to two substituents that are selected, independently, from (C1-C6)alkyl, amino, (C1-C6) alkylamino, [di-(C1-C6)alkyllamino, phenyl substituted 5 to 6 membered heterocyclic rings containing from 1 to 4 rings nitrogen atoms, benzoyl, benzoylmethyl, benzylcarbonyl, phenylaminocarbonyl, phenylethyl and phenoxycarbonyl, and wherein the phenyl moieties of any of the foregoing substituents may optionally be substituted with one or more substituents, preferably with from zero to two substituents, that are selected, independently, from halo, (C1-C3)alkyl, (C1-C3)alkoxy, nitro, amino, cyano, CF3 and OCF3;
n is 0, 1 or 2;
m is 0, 1, or 2;
each R8 and each R9 is selected, independently, from (C1-C4)alkyl, aryl-(C1-C4)alkyl wherein said aryl is selected from phenyl and naphthyl; allyl and phenallyl;
X and Y are selected, independently, from methyl, methoxy, hydroxy and hydrogen; and
R10 is (C1-C6) alkyl;
with the proviso that R8 is absent when N is zero and R9 is absent when m is zero.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and Pamoate [i.e., 1, 1-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9cone or more substituentsxe2x80x9d, as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
Examples of preferred compounds of this invention are compounds of the formula I, and their pharmaceutically acceptable salts, wherein NR1R2 is:
4-phenoxycarbonylpiperazin-1-yl;
4-(4-fluorophenylacetyl)piperazin-1-yl;
4-phenylethylpiperazin-1-yl;
4-phenoxymethylcarbonylpiperazin-1-yl;
4-phenylaminocarbonylpiperazin-1-yl;
4-benzoylmethylpiperazin-1-yl; or 4-benzylcarbonylpiperazin-1-yl.
Other preferred compounds of this invention are compounds of the formula I, and their pharmaceutically acceptable salts, wherein NR1R2 is a group of the formula 
wherein NR3R4 is NH2.
Other preferred compounds of this invention are compounds of the formula I, and their pharmaceutically acceptable salts, wherein NR1R2 is a group of the formula 
wherein R5 is aralkyl, e.g., benzyl, and R6 is (4-fluoro)phenylacetyl.
Specific preferred compounds of the present invention include the following:
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-methoxy-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin- 1-yl)-2-phenoxy-ethanone;
(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-cyclopentyl-methanone;
1(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone;
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.10]hex-6-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluoro-phenyl)-ethanone;
6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanol;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;
6-{4-(2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine;
6-{4-[2-(4-Amino-2, 6-dimethyl-piperidin-1-yl)-ethyll-phenyl}-pyridin-2-ylamine;
6-{4-[2-(4-Methyl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
(3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-dimethyl-amine;
6-[4-(2-Amino-ethyl)-phenyl]-pyridin-2-ylamine;
6-{4-[2-(8-Aza-spiro[4.5]dec-8-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-[2-(4-1sobutyl-piperazin-1-yI)-ethyl]-phenyl}-pyridin-2-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-N-isopropyl-acetamide;
4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazine-1-carboxylic acid p-tolyl-amide;
6-(4-{2-[4-(3-Phenyl-propyl)-piperazin-1-yl]-ethyl}-phenyl)-pyridin-2-ylamine;
1-{4-(2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-2-(4-chloro-phenyl)-ethanone;
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-benzyl-1, 3, 8-triaza-spiro[4.5]decane-2, 4-dione;
N-(1-2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl)-pyrrolidin-3-yl)-2-(4-fluoro-phenyl)-acetamide;
8-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-ylamine;
3-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-3-aza-bicyclo[3.2.1]oct-8-ylamine;
2-Amino-1-(4-{2-[4-(6-amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-3-phenyl-propan-1-one;
6-{4-[2-(4-Amino-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-[2-(4-Benzhydryl-piperazin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-[2-(4-Benzhydryl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-[(Cyclohexyl-methyl-amino)-methyl]-phenyl}-pyridin-2-ylamine;
6-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-methoxy-phenyl}-pyridin-2-ylamine;
6-(4-(Phenethylamino-methyl)-phenyl]-pyridin-2-ylamine;
6-[2-Methoxy-4-(phenethylamino-methyl)-phenyl]-pyridin-2-ylamine;
6-[4-(4-Amino-piperidin-1-ylmethyl)-phenyl}-pyridin-2-ylamine;
6-{4-[(Cyclohexyl-methyl-amino)-methyl]-2-fluoro-phenyl}-pyridin-2-ylamine;
Other compounds of the formula I include:
1-(4-{2-4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone;
6-{4-[2-(4-Isobutyl-piperazin-1-yl)-ethyl]-2-methoxy-phenyl}-pyridin-2-ylamine;
3-{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamine;
{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;
6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-2-methoxy-phenyl)-pyridin-2-ylamine;
6-{4-[2-(4-Amino-2-methoxy-piperidin-1-yl)-ethyl]-2-methoxy-phenyl}-pyridin-2-ylamine;
2-(4-{2-]4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-N-isopropyl-acetamide;
6-[4-(4-Amino-piperidin-1-ylmethyl)-2-methoxy-phenyl}-pyridin-2-ylamine;
1-{4-(2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone;
6-{4-[2-(4-Isobutyl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-pyridin-2-ylamine;
3-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanone;
1-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluoro-phenyl)-ethanone;
6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-pyridin-2-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanol;
{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;
6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-2-methyl-phenyl)-pyridin-2-ylamine;
6-{4-[2-(4-Amino-2, 6-dimethyl-piperidin-1-yl)-ethyl]-2-methyl-phenyl}-pyridin-2-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methyl-phenyl]-ethyl}-piperazin-1-yl)-N-isopropyl-acetamide;
6-[4-(4-Amino-piperidin-1-ylmethyl)-2-methyl-phenyl}-pyridin-2-ylamine;
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-phenyl-acetamide;
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(3-trifluoromethyl phenyl)-acetamide;
N-(1{2-[4-(6-Amino-pyridin-2-yl )-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(4-tolyl)-acetamide;
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-(4-methoxyphenyl)-acetamide;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-methoxy-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluoro-phenyl)-ethanone;
N-(1-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-pyrrolidin-3-yl)-2-cyclohexyl-acetamide;
2-(4-{2-4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-tolyl)-ethanone;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-methoxyphenyl)-ethanone;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-chlorophenyl)-ethanone;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-(4-fluorophenyl)-ethanone;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-piperazin-1-yl)-1-cyclohexyl-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-2-phenyl-ethanone;
6-{4-[2-(4-isobutyl-piperazin-1-yl)-ethyl]-2-fluoro-phenyl}-pyridin-2-ylamine;
3-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-3-aza-bicyclo[3.1.0]hex-6-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanone;
1-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-2-(4-fluoro-phenyl)-ethanone;
6-{4-[2-(4-Phenethyl-piperazin-1-yl)-ethyl]-2-fluoro-phenyl}-pyridin-2-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-1-phenyl-ethanol;
{2-[4-(6-Amino-pyridin-2yl)-2fluoro-phenyl]-ethyl}-(3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;
6-(4-{2-[4-(2-Amino-2-phenyl-ethyl)-piperazin-1-yl]-ethyl}-2-fluoro-phenyl)-pyridin-2-ylamine;
6-{4-[2-(4-Amino-2-fluoro-piperidin-1-yl)-ethyl]-2-fluoro-phenyl}-pyridin-2-ylamine;
2-(4-{2-[4-(6-Amino-pyridin-2-yl)-2-fluoro-phenyl]-ethyl}-piperazin-1-yl)-N-isopropyl-acetamide;
6-[4-(4-Amino-piperidin-1-ylmethyl)-2-fluoro-phenyl}-pyridin-2-ylamine;
6-{4-[2-(4-Amino-2, 6-diethyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
6-{4-(2-(4-Amino-2, 6-dibenzyl-piperidin-1-yl)-ethyl]-phenyl}-pyridin-2-ylamine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-fluoro)-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-chloro)-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine;
{2-[4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-methyl)-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine; and
{2-(4-(6-Amino-pyridin-2-yl)-phenyl]-ethyl}-(9-(4-methoxy)-benzyl-3-oxa-9-aza-bicyclo[3.3.1]non-7-yl)-amine.
The present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of migraine inflammatory diseases (e.g., asthma), stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn""s disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer""s disease, chemical dependencies and addiction (e.g., dependencies on drugs, alcohol and nicotine), emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington""s disease, Parkinson""s disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephropathy and cancer in a mammal, including a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof that is effective in treating or preventing such condition, and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or preventing a condition selected from the group consisting of migraine inflammatory diseases (e.g., asthma), stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn""s disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer""s disease, chemical dependencies and addictions (e.g., dependencies on drugs, alcohol and nicotine), emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington""s disease, Parkinson""s disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephropathy and cancer in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such condition.
The present invention also relates to a pharmaceutical composition for inhibiting nitric oxide synthase (NOS) in a mammal, including a human, comprising an NOS inhibiting effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The present invention also relates to a method of inhibiting NOS in a mammal, including a human, comprising administering to said mammal a NOS inhibiting effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.
The present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of migraine, inflammatory diseases (e.g., asthma), stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn""s disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer""s disease, chemical dependencies and addictions (e.g., dependencies on drugs, alcohol and nicotine), emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington""s disease, Parkinson""s disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephropathy and cancer in a mammal, including a human, comprising a NOS inhibiting effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
The present invention also relates to a method of treating or preventing a condition selected from the group consisting of migraine, inflammatory diseases (e.g., asthma), stroke, acute and chronic pain, hypovolemic shock, traumatic shock, reperfusion injury, Crohn""s disease, ulcerative colitis, septic shock, multiple sclerosis, AIDS associated dementia, neurodegenerative diseases, neuron toxicity, Alzheimer""s disease, chemical dependencies and addictions (ec.a, dependencies on drugs, alcohol or nicotine), emesis, epilepsy, anxiety, psychosis, head trauma, adult respiratory distress syndrome (ARDS), morphine induced tolerance and withdrawal symptoms, inflammatory bowel disease, osteoarthritis, rheumatoid arthritis, ovulation, dilated cardiomyopathy, acute spinal cord injury, Huntington""s disease, Parkinson""s disease, glaucoma, macular degeneration, diabetic neuropathy, diabetic nephropathy and cancer in a mammal, including a human, comprising administering to said mammal a NOS inhibiting effective amount of a compound of the formula II, or a pharmaceutically acceptable salt thereof.
Compounds of formula I have chiral centers and therefore may exist in different enantiomeric and diastereomic forms. This invention relates to all optical isomers and all stereolsomers of compounds of the formula I and mixtures thereof, and to all pharmaceutical compositions and methods of treatment defined above that contain or employ them, respectively.
Formulae I and II above include compounds identical to those depicted but for the fast that one or more hydrogen, carbon or other atoms are replaced by isotopes thereof. Such compounds may be useful as research and diagnostic tools in metabolism pharmacokinetic studies and in binding assays.
The compounds of the formula I may be prepared as described in the following reaction schemes and discussion. Unless otherwise indicated, R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 and structural formula I in the reaction schemes and discussion that follow are defined as above. 
The starting materials used in the procedure of Scheme 1 are either commercially available, known in the art or readily obtainable form known compounds by methods that will be apparent to those skilled in the art. Referring to Scheme 1, the conversion of the compound of formula II into the compound of formula III may be carried out by first converting the compound of formula II into the corresponding 2-amino compound by reacting it with ammonia in a polar hydroxylic or polar nonhydroxylic solvent at a temperature of about 100xc2x0 C. to about 250xc2x0 C. and a pressure of about 50 to about 500 p.s.i. for about 1 to 24 hours, preferably using a stainless steel bomb. The pyrrolyl group is then added using hexane-2,5-dione, either neat or in a non-polar solvent such as toluene, in the presence of an acidic catalyst such as acetic acid or hydrochloric acid, at a temperature from about room temperature to about the reflux temperature, generally the latter, for about 1 to 72 hours.
The conversion of the compound of formula III formed in the above reaction into the compound of formula IV is carried out using a transition metal mediated coupling reaction with a suitably substituted aryl iodide or bromide. More specifically, the lithium derivative of the compound of formula III is generated in an ethereal or hydrocarbon solvent at a temperature from about xe2x88x92100xc2x0 C. to about room temperature, preferably at about xe2x88x9278xc2x0 C., using an alkyl lithium such as butyl lithium, for about 10 to 120 minutes, followed by addition of a catalytic metal reagent such as zinc chloride and warming to room temperature to effect transmetalation. This is followed by addition of the aryl iodide (e.g., 1-iodo-4-(2-chloroethyl)benzene) or bromide and a transition metal, such as palladium in the form of tetrakistriphenylphosphine palladium, followed by heating to a temperature of about 30xc2x0 C. to about 100xc2x0 C., typically to about the reflux temperature of the solvent, for about 1 to 24 hours.
The conversion of the compound of formula IV to the desired compound of formula I is accomplished by first removing the pyrrolyl protecting group using, typically, hydroxylamine or hydroxylamine hydrochloride in a polar, protic solvent such as an alcohol, at a temperature of from about room temperature to about 150xc2x0 C., generally at about the reflux temperature of the solvent, for about 1 to 72 hours. This is followed by addition of the appropriate NR1R2 group by displacement of the chloro group with an amine of the formula HNR1R2 using a polar, aprotic or a polar, protic solvent such as an alcohol, dimethylformamide (DMF), methylisobutylketone or N-methylpyrrolidone (NMP), optionally in the presence of a catalyst such as sodium iodide, at a temperature of from about room temperature to about 200xc2x0 C., typically at about the reflux temperature of the solvent, or at about 140xc2x0 C. in the cases of dimethylformamide and N-methylpyrrolidone, for about 100 hours, generally from about 12 to 24 hours.
Referring to Scheme 2, compound VI is prepared by reacting V with p-formylbenzeneboronic acid in a solvent consisting of an alcohol, preferably ethanol, optionally mixed with water of a halogenated hydrocarbon, at a temperature from 25xc2x0 C. to 150xc2x0 C., for a time from 1 to 24 hours, using a palladium-based catalyst, either palladium-zero or palladium-two oxidation state, typically with phosphine ligands, preferably tetrakis-triphenylphosphine palladium. Compound VII is prepared by reacting VI with tosylmethylisocyanide in the presence of potassium t-butoxide and ethanol, in an ethereal solvent such as 1, 2-dimethoxyethane, at a temperature from xe2x88x92100xc2x0 C. to 100xc2x0 C., for a time from 1 to 24 hours. Compound VIII is prepared from VII by basic hydrolysis of the nitrile using an alkali metal hydroxide in an aqueous alcohol-based solvent, such as aqueous ethanol, at a temperature from 25xc2x0 C. to 125xc2x0 C., for a time from 30 minutes to 48 hours. Compound IX is prepared from VIII by dehydrative coupling with ammonia, a primary amine, or a secondary amine effected by a dehydrating agent such as a carbodiimide, for example, N-ethyl-N-(dimethylaminopropyl)-carbodiimide, in a solvent from a halogenated hydrocarbon or N,N-dialkylamide, such as dimethylformamide, at a temperature from 0xc2x0 C. to 100xc2x0 C., for a time from 1 to 48 hours. Compound X is prepared from IX by deblocking using hydroxylamine hydrochloride in an aqueous or alcoholic solvent, preferably aqueous ethanol, at a temperature from 25xc2x0 C. to 100xc2x0 C., for a time from 1 to 48 hours, and may include deblocking a protecting group such a the t-butoxycarbonyl group, by reaction with trifluoroacetic acid, or a related polyhalogenated acetic acid, or a gaseous hydrogen halide, such as HCl, in a halogenated hydrocarbon, ethereal solvent or ethyl acetate, at a temperature from xe2x88x9270xc2x0 C. to 100xc2x0 C., for a time from 10 minutes to 24 hours. The final compound in Scheme 2, I, is prepared by reduction of X with borane, a trialkyl borane, alane, or lithium aluminum hydride in an ethereal solvent, such as ethyl ether or tetrahydrofuran, at a temperature from xe2x88x92100xc2x0 C. to 100xc2x0 C., for a time from 30 minutes to 24 hours, and optionally using cesium fluoride and an alkali metal or alkaline earth carbonate in an aqueous alcoholic solvent, at a temperature from 25xc2x0 C. to 125xc2x0 C. for a time from 1 to 72 hours.
Referring to Scheme 3, compound XI is prepared by dehydrative coupling of N-phenethylpiperazine with 4-bromophenylacetic acid using a carbodiimide-based dehydrating reagent, such as N-ethyl, N-(dimethylaminopropyl)-carbodiimide, in a solvent such as a halogenated hydrocarbon or dialkylamide-based solvent, such as dimethylformamide, at a temperature from 0xc2x0 C. to 100xc2x0 C. in a time from 1 to 48 hours. Compound XI was converted to compound XII by reduction with borane, a trialkyl borane, alane, or lithium aluminum hydride in an ethereal solvent, such as ethyl ether or tetrahydrofuran, at a temperature from xe2x88x92100xc2x0 C. to 100xc2x0 C., for a time from 30 minutes to 24 hours, and optionally using cesium fluoride and an alkali metal or alkaline earth carbonate in an aqueous alcoholic solvent, at a temperature from 25xc2x0 C. to 125xc2x0 C. for a time from 1 to 72 hours. Compound XII is then converted to the organolithium derivative in the presence of an organolithium reagent, such as butyl lithium, and added to 4-methyl-2-(2, 5-dimethylpyrrolyl)-pyridine in an ethereal solvent, such as ethyl ether, at a temperature from xe2x88x9270xc2x0 C. to 70xc2x0 C. in a time from 30 minutes to 24 hours. The final compound in Scheme 3, compound I, is prepared by deblocking using hydroxylamine hydrochloride in an aqueous or alcoholic solvent, preferably aqueous ethanol, at a temperature from 25xc2x0 C. to 100xc2x0 C., for a time from 1 to 48 hours.
Referring to Scheme 4, compound XIV is prepared by dehydrative coupling of dibenzylamine with 4-bromophenylacetic acid effected by a dehydrating agent such as a carbodiimide, for example, N-ethyl-N-(dimethylaminopropyl)-carbodiimide, in a solvent from a halogenated hydrocarbon or N,N-dialkylamide, such as dimethylformamide, at a temperature from 0xc2x0 C. to 100xc2x0 C., for a time from 1 to 48 hours. Compound XIV is converted to compound XV by reduction with borane, a trialkyl borane, alane, or lithium aluminum hydride in an ethereal solvent, such as ethyl ether or tetrahydrofuran, at a temperature from xe2x88x92100xc2x0 C. to 100xc2x0 C., for a time from 30 minutes to 24 hours, and optionally using cesium fluoride and an alkali metal or alkaline earth carbonate in an aqueous alcoholic solvent, at a temperature from 25xc2x0 C. to 125xc2x0 C. for a time from 1 to 72 hours. Compound XV is then converted to the organolithium derivative in the presence of an organolithium reagent, such as butyl lithium, and added to 2-(2, 5-dimethylpyrrolyl)-pyridine in an ethereal solvent, such as ethyl ether, at a temperature from xe2x88x9270xc2x0 C. to 70xc2x0 C. in a time from 30 minutes to 24 hours to provide compound XVI. Compound XVII is then prepared from compound XVI by hydrogenolysis with hydrogen or ammonium formate in the presence of a noble metal catalyst, such as palladium, in an ethereal, halogenated hydrocarbon, alcoholic, or aqueous alcoholic solvent, at a temperature from 0xc2x0 C. to 100xc2x0 C. for a time from 30 minutes to 24 hours. Compound XVIII is then prepared from compound XVII by reductive amination with an aldehyde or ketone in the presence of a borohydride-based reagent such as sodium cyanoborohydride or sodium triacetoxyborohydride, in an ethereal, halogenated hydrocarbon, alcoholic, or aqueous-alcoholic solvent, at a temperature from 0xc2x0 C. to 100xc2x0 C. for a time from 1 to 72 hours. Conversion of compound XVIII to I by deblocking is carried out by using hydroxylamine hydrochloride in an aqueous or alcoholic solvent, preferably aqueous ethanol, at a temperature from 25xc2x0 C. to 100xc2x0 C., for a time from 1 to 48 hours.
Referring to Scheme 5, compound XIX is prepared by reaction of the known (EP 470794 A1, see Chem. Abs., 116:193935) 2-bromo-5-methylanisole with an alkyl lithium, typically butyl lithium, in an ethereal or hydrocarbon solvent, at a temperature from xe2x88x92100xc2x0 C. to 0xc2x0 C. for 1 minute to 24 h, followed by addition of an alkyl or aryl borate ester, typically triethyl borate, at a temperature from xe2x88x92100xc2x0 C. to 0xc2x0 C., and stirred while the temperature was adjusted to 0xc2x0 C. to the reflux temperature of the solvent, typically 65xc2x0 C., for 1 to 48 hours. Compound XIX is converted to XX by reaction with 6-bromo-2-(2, 5-dimethylpyrrolyl)pyridine and an alkali carbonate in a solvent consisting of an alcohol, preferably ethanol, optionally mixed with water of a halogenated hydrocarbon, at a temperature from 25xc2x0 C. to 150xc2x0 C., for a time from 1 to 24 hours, using a palladium-based catalyst, either palladium-zero or palladium-two oxidation state, typically with phosphine ligands, preferably tetrakis-triphenylphosphine palladium. Compound XXI was prepared from XX by first deblocking using hydroxylamine hydrochloride in an aqueous or alcoholic solvent, preferably aqueous ethanol, at a temperature from 25xc2x0 C. to 100xc2x0 C., for a time from 1 to 48 hours, followed by reaction with N-carbethoxyphthalimide in a hydrocarbon solvent at a temperature from room temperature to the reflux temperature of the solvent or 180xc2x0 C., typically 110xc2x0 C., for a time from 1 to 48 hours. Conversion of compound XXI to XXII was carried out by reaction with N-bromo succinimide in a chlorinated hydrocarbon solvent, typically carbon tetrachloride, with a catalytic amount of a radical initiator such as azobisisobutyronitrile, at a temperature from room temperature to 100xc2x0 C. for a time from 10 minutes to 24 hours. Compound XXII was then converted to XXIII by reaction with an amine, such as phenethylamine, in a hydrocarbon, halogenated hydrocarbon, ethereal, or polar aprotic solvent, such as acetonitrile, with an alkali carbonate base, at a temperature from room temperature to 100xc2x0 C. for a time from 10 minutes to 48 hours. Compound XXIII was then converted to the final product in Scheme 5, I, by deblocking using hydrazine in an alcoholic, aqueous, or ethereal solvent, at a temperature from room temperature to 150xc2x0 C. for a time from 1 to 72 hours.
The preparation of other compounds of the formula I not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
In each of the reactions discussed or illustrated above, pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally acceptable, and ambient pressure, i.e., about 1 atmosphere, is preferred as a matter of convenience.
The compounds of formulae I (xe2x80x9cthe active compounds of this inventionxe2x80x9d) which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the active base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
The active compounds of this invention and their pharmaceutically acceptable salts are useful as NOS inhibitors i.e., they possess the ability to inhibit the NOS enzyme in mammals, and therefore they are able to function as therapeutic agents in the treatment of the aforementioned disorders and diseases in an afflicted mammal.
The active compounds of this invention and their pharmaceutically acceptable salts can be administered via either the oral, parenteral or topical routes. In general, these compounds are most desirably administered in dosages ranging from about 0.01 to about 250 mg per day, in single or divided doses (i.e., from 1 to 4 doses per day), although variations will necessarily occur depending upon the species, weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.07 mg to about 21 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the three routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutically-effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfatesand talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of an active compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8) if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
Additionally, it is also possible to administer the active compounds of the present invention topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes, patches, ointments and the like, in accordance with standard pharmaceutical practice.
The ability of compounds of the formulae I to inhibit NOS may be determined using procedures described in the literature. The ability of compounds of the formulae I to inhibit endothelial NOS may be determined by using the procedures described by Schmidt et al. in Proc. Natl. Acad. Sci. U.S.A., 88, pp. 365-369 (1991) and by Pollock et al., in Proc. Natl. Acad. Scd. U.S.A., 88, pp. 10480-10484 (1991 The ability of compounds of the formulae I to inhibit inducible NOS may be determined using the procedures described by Schmidt et al., in Proc. Natl. Acad, Sci. U.S.A., 88 pp. 365-369 (1991) and by Garvey et al. in J. Biol. Chem., 269, pp. 26669-26676 (1994). The ability of the compounds of the formula I to inhibit neuronal NOS may be determined using the procedure described by Bredt and Synder in Proc. Natl. Acad. Sci. U.S.A., 87, 682-685 (1990).
Of 100 compounds of the formula I that were tested, all exhibited an IC50 less than 10 xcexcM for inhibition of either inducible or neuronal NOS.
The present invention is illustrated by the following examples. It will be understood, however, that the invention is not limited to the specific details of these examples. Melting points are uncorrected. Proton nuclear magnetic resonance spectra (1H NMR) and C13 nuclear magnetic resonance spectra were measured for solutions in deuterochloroform (CDCl3) or in CD3OD or CD3SOCD3 and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane (TMS). The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet, m, multiplet, b, broad.